Innovation: Editing Out Disease

Announcer: Examining the latest research and telling you about the latest breakthroughs. The Science and Research Show is on The Scope.

Julie Kiefer: My guest Dr. Ryan O'Connell, Professor in Pathology, was recently awarded the National Institutes of Health New Innovator Award for high risk, high impact research. So how did it feel to get the announcement of that award?

Dr. Ryan O'Connell: It felt great. It was very competitive, so you didn't know what to expect. It was very surprising to get the good news. It took a few minutes to set in, but once I realized that I was going to receive the award, I was incredibly grateful and excited.

Julie Kiefer: Your research concerns micro-RNAs. Can you explain what a micro-RNA is and what it does?

Dr. Ryan O'Connell: Sure. Micro-RNA is a small RNA that instead of encoding or producing a protein, the micro-RNA itself has a function within the cell. This function, at least the function that we understand the most, is to reduce the level of specific proteins in the cell.

Julie Kiefer: Have they been implicated in disease, as well?

Dr. Ryan O'Connell: Absolutely. Actually, that's where micro-RNAs were rediscovered, so to speak. They're found to be expressed at aberrant levels in certain types of cancers. That really started this whole wave of trying to understand what micro-RNAs are. Now we know that they are altered in disease states such as cancer, auto-immunity and cardiovascular disease. What happens is by their levels changing, the pathways that they control now become out of whack and that can really either cause or enhance disease states.

Julie Kiefer: The research that you're doing in association with this award involves actually regulating these regulators. Can you explain how you're doing that?

Dr. Ryan O'Connell: Micro-RNAs are clearly really important in driving cancer phenotypes, in driving auto-immunity and a lot of this knowledge has come from work that we've done in mice. I've become really interested in trying to move our studies into some human, pre-clinical models. For the grand proposal, the idea was to take this TALEN technology, which again is a molecular machine that can specifically alter precise locations in the human genome and delete genes in human cells, was to use this technology to be able to delete the micro-RNA genes that we know are important for disease. So we wanted to bridge the TALEN technology with our knowledge of what micro-RNAs can do and their role in cancer and auto-immunity.

Julie Kiefer: So in the lab you can genetically engineer the TALEN protein to edit specific sequences, then you introduce those TALEN proteins into the cell and they do their job.

Dr. Ryan O'Connell: That's right. So the TALEN can be designed to bind to any sequence of DNA, and then once bound, you can attach additional machinery that can actually delete precise pieces of the genome. Again, we wanted to use this to be able to delete segments of the micro-RNA genes that we study.

Julie Kiefer: So beyond validating what's already been done in mice, could this be a new type of therapy?

Dr. Ryan O'Connell: Exactly. In addition to seeing if our results really translate, I really believe this technology could be developed even further and used as a therapy. If you have, for example, a cancer that is dependent on the over-expression of a micro-RNA, can we now use the TALEN technology to reduce or eliminate the micro-RNA gene that's the driving force behind the disease.

Julie Kiefer: It's hard to imagine how this would actually work, and maybe that's work in progress. How would you actually get these TALENs into a person?

Dr. Ryan O'Connell: Right. We work with the hematopoietic system or the blood system or the blood system. The nice thing about working with that is that the hematopoietic stem cell has been well characterized. So we routinely can take a hematopoietic stem cell and reconstitute a persons entire blood system. This is done all the time, therapeutically. It's also true that it's possible to take the TALENs and to introduce these into the hematopoietic stem cell so that the TALEN could modify its target and then what we want to design it to do is modify the micro-RNA gene. Then we put these stem cells, potentially, into people, and then when the stem cell gives rise to the blood system, we can now create a blood system where we've removed the driving force of the disease.

Julie Kiefer: So you would add these TALEN proteins into the stem cells outside of the body and then reintroduce them through transfusion or something like that.

Dr. Ryan O'Connell: That's one approach, right. That's correct.

Julie Kiefer: Okay.

Dr. Ryan O'Connell: You could also, if you wanted to prevent auto-immunity, instead of going through the stem cell you could take the T-lymphocyte, which is the causing force of the auto-immune disease, and introduce the TALEN into the T-cell outside of the body and then also infuse the T-cells back in as another alternative.

Julie Kiefer: That's really fascinating. It's like a radically new type of therapy. What's interesting is that the TALEN protein comes from plants, right?

Dr. Ryan O'Connell: That's right.

Julie Kiefer: So you'd be introducing a plant gene...

Dr. Ryan O'Connell: It's from a plant pathogen, a bacteria.

Julie Kiefer: A plant pathogen? Okay. So you'd be introducing that foreign gene into humans and that would be carrying out essentially genetic engineering in human cells. How do you think people will receive that?

Dr. Ryan O'Connell: Although the TALEN proteins basically were first identified in the plant bacterial pathogen, the amino acids that the TALENs are actually comprised of are the same nucleic acids that are found in human cells already. We would basically just be introducing a specific new type of protein, again comprised of the same kind of molecules that are already in our cells, and stringing those together in a specific way were we could enable the function of the TALEN, which is the genome editing, to occur.

Julie Kiefer: So you don't foresee the media taking this out of proportion and saying there's genetic engineering in humans? There's such a phobia of that in our food.

Dr. Ryan O'Connell: Right. I think if people can understand the specifics of what we're doing here, I don't think they'll be concerned. Were not going to be transferring microbes or entire organisms into people. We're simply taking a design that's found in these particular bacteria and then using that design in these particular molecules and re-engineering it so that it can be useful in our cells.

Julie Kiefer: When I think of different types of therapies, another one that comes to mind is the magic bullet, which are antibodies that target specific disease cells. How does this technology compare to that?

Dr. Ryan O'Connell: Antibodies are very useful to eliminate cells that are dangerous or causing disease. They can also be used to deliver cargo to specific cell types. So antibodies absolutely have their place, but antibodies do not have the ability to get inside the cell and correct genes that have become mutated and that are the causing force or the foundation of the disease that's happening in people. Whereas with the TALEN, it's a completely different concept. The TALEN again is a molecular machine, that if we can design it correctly and deliver it properly to the right cells, can actually go in and fix problems and mistakes in your DNA sequence and in so doing, can fix the foundation and the cause of the disease that the person is suffering from.

Julie Kiefer: Why do you believe in this research? What's motivated you to take this path?

Dr. Ryan O'Connell: I do think that at the end of the day, it's pretty clear that genetics plays a huge role in most types of human disease. I think in many cases we're beginning to understand the nature of the types of variations in gene sequence and mutations that occur and how those result in the problems that a lot of us face. So I think while a lot of therapies are more band-aids to try to treat the symptoms of a disease, I do believe that through genome editing and hitting the most important genes, which I believe include micro-RNAs, we can actually fix the cause of disorders that happen. It's applicable not only to cancer, but to auto-immunity, cardiovascular disease and just about any disease that we face as people.

Julie Kiefer: What else can you use TALENs for, besides combating different disease?

Dr. Ryan O'Connell: If you want to get creative, it's possible that one day once we understand things a whole lot better that we could use genome editing to change any trait that a person might have by being able to make precise alterations to the relevant genes that control different traits that we have.

Julie Kiefer: Wow.

Dr. Ryan O'Connell: This is pie in the sky stuff at this point.

Julie Kiefer: Yeah. Sure.

Dr. Ryan O'Connell: But I think everything starts with an idea and then you work hard and you try to overcome the obstacles. I think there's a lot of demonstration of ideas turn into discoveries that turn into everyday therapies and things that we can use to better our lives.

Announcer: Interesting, informative and all in the name of better health. This is The Scope Health Sciences Radio.